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CMR Detects Subclinical Cardiomyopathy in Mother-Carriers of Duchenne and Becker Muscular Dystrophy

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CMR Detects Subclinical Cardiomyopathy in Mother-Carriers of Duchenne and Becker Muscular Dystrophy
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  L E T T E R S T O T H E E D I T O R CMR Detects SubclinicalCardiomyopathy in Mother-Carriers of Duchenne andBecker Muscular Dystrophy Duchenne muscular dystrophy (DMD) is an X-linked reces-sive disorder, leading to reduced/abnormal dystrophin. Beckermuscular dystrophy (BMD) is a milder form, caused by thesame mutation, with a nearly normal life expectancy, but witha 50% chance of cardiac involvement (CI) (1). Althoughfemale carriers are usually free of symptoms, they may developperipheral myopathy and cardiomyopathy, contributing toheart failure (HF) (1).Our aim was to evaluate the possibility of myocardialdamage in genetically confirmed mothers-carriers of Duch-enne muscular dystrophy (DMDc) and Becker muscular dys-trophy (BMDc) using cardiac magnetic resonance (CMR). Thirty-five mothers, mean age 50 years (range: 32 to 68 years), without known comorbidities, except mild hyperten-sion (systolic blood pressure 160 to 170 mm Hg in 1 DMDcand 1 BMDc), were studied. DMDc (n    25) and BMDc(n  10) were prospectively evaluated by CMR using a 1.5-TGeneral Electric Signa HDxt (Milwaukee, Wisconsin). Astandard steady-state free-precession (SSFP) sequence (FI-ESTA) (echo time    1.5 ms, repetition time    3.1 ms, flipangle  70°, slice thickness  8 mm) was used to measure theleft ventricular ejection fraction (LVEF). To assess fibrosis, 0.2mmol/kg gadolinium diethylenetriamine penta-acetic acid wasadministered, and late gadolinium-enhanced (LGE) images were taken 15 min later, using a 3-dimensional–T1-turbo fieldecho sequence (flip angle    15°, echo time    1.4 ms,repetition time    5.5 ms, inversion time 225 to 275 ms asindividually optimized to null myocardial signal, gap  0, slicethickness  6 mm). A threshold of   6 SD exceeding the mean was used to define LGE images (2). Summing the planimeteredLGE areas in all short-axis slices yielded the total volume,expressed as a proportion of left ventricular (LV) myocardium(percentage of LGE).Measurements were expressed as mean    SD or mean(range). Statistical significance was investigated by unpairedStudent  t   test. Correlation was sought with Pearson correla-tion coefficient. The Mann-Whitney test and Spearman cor-relation coefficient were used for nonparametric data. Statis-tical significance was considered p  0.05.Eight DMDc and 1 BMDc presented with muscle weakness,recognized by the subjects, but which did not affect daily activities. Cardiac symptoms were documented only in 5 of 25DMDc. Creatine kinase (CK) was measured in all carriers. CK  values of 290    120 IU/l (normal values   190 IU/l) wereidentified in 15 of 35 (42.8%) carriers (13 [52%] DMDc and 2[20%] BMDc). CMR documented decreased LVEF in 10DMDc and subepicardial LGE images in posterolateral and/orseptal LV wall in 18 DMDc and 5 BMDc (Figs. 1 and 2). No difference in LGE morphology was identified between DMDcand BMDc. LGE images correlated negatively with LVEF (p  0.001) and were greater in DMDc compared with BMDc(16    2% vs. 3    1%, p    0.001, respectively). Carriers   40 years old had more extensive lesions compared with those  40 years old (14    2% vs. 3    1%, p    0.001). The lack of comorbidities that could be possibly related to CMR findingsstrengthenstheroleofabnormaldystrophinintheirpathogenesis.Carriers’ characteristics are presented in Table 1. According to previous studies, 12% of BMDc presented with muscle weakness, and CK was increased in 30% to 62%(1,3,4). In our study, although some BMDc had muscularsymptoms and increased CK, the majority was asymptomatic with normal CK. The prevalence of CI on electrocardiography (ECG) and echocardiography and the possibility of dilated Figure 1. Late Gadolinium-Enhanced Image of a Becker MuscularDystrophy Carrier With Mild Epicardial Fibrosis in the Lateral Wall of theLeft VentricleFigure 2. Late Gadolinium-Enhanced Image of a Duchene MuscularDystrophy Carrier With Severe Epicardial Fibrosis in the Lateral Wall of the Left Ventricle J A C C : C A R D I O V A S C U L A R I M A G I N G V O L . 6 , N O . 4 , 2 0 1 3© 2 0 1 3 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N I S S N 1 9 3 6 - 8 7 8 X / $ 3 6 . 0 0P U B L I S H E D B Y E L S E V I E R I N C .  cardiomyopathy (dCMP) varied widely (3,4). CI in BMDc appearsafter the age of 16 years and may remain subclinical with advancingage in up to two-thirds of subjects. It can be manifested as ECGchanges in two-fifths or as dCMP in up to one-fifth of cases (3).Our BMDc findings were in agreement with previous studiesidentifying normal ECG and echocardiographic results in themajority of subjects.DMDc are more likely to develop dCMP at a young age (3). A2002 consensus estimated that 10% of all DMDc or BMDc developdCMP, even without skeletal muscle involvement (3). However,the impact of increased dCMP risk on life expectancy is still unclear(3). Although only a minority of our patients presented withmuscular involvement, some DMDc already had LV impairmentand rhythm disturbances. These findings were in agreement withprevious studies supporting that CI is independent of musculardisturbances in DMDc (3).Recently, CMR has been successfully used to identify myocardialfibrosis in subclinical DMDc or BMDc (4,5). However, except forcase reports (4,5), there are not enough data about CMR indystrophinopathy carriers. In our study, we identified myocardialfibrosis in the majority of carriers, with a significant superiority inseverity of DMDc over BMDc and older carriers over youngercarriers. The inverse correlation of fibrotic area, identified by LGEimaging, with LVEF supports the role of fibrosis in the develop-ment of HF (1,2). Furthermore, CMR proved to be of greatsignificance documenting CI in a percentage higher than thatidentified by routine assessment. The study limitations were that the population of studied carriers was small, young female carriers were not included, and long-termfollow-up was not available. To conclude, CMR documented myocardial fibrosis in the majority of dystrophinopathy carriers, although the usual assessment was mildly abnormal. However, the clinical implications of CMR and the neces-sity for early cardiac treatment need further evaluation. Sophie Mavrogeni, MD*, Konstantinos Bratis, MD,Antigoni Papavasiliou, MD, Eleni Skouteli, MD,Evangelos Karanasios, MD, Dimitris Georgakopoulos, MD,Genovefa Kolovou, MD, George Papadopoulos, MD *Onassis Cardiac Surgery Center, 50 Esperou Street,175-61 P. Faliro, Athens, Greece.  E-mail: soma13@otenet.gr  http:dx.doi.org/10.1016/j.jcmg.2012.09.017 Table 1. DMDc and BMDc Clinical Characteristics and ComorbiditiesDMD (n  25) BMD (n  10) Age (yrs) (median, range) 48 (33–65) 52 (31–69)Height (cm) (median, range) 170 (158–175) 168 (160–172)Weight (kg) (median, range) 70 (62–78) 74 (65–80)Diabetes mellitus 0 0Hypertension (SBP 160–170 mm Hg) 1/25 1/10Dyslipidemia 0 0Smoking 0 0Alcohol consumption 0 0Infections that could possibly induce myocardial damage 0 0Valvular disease 0 0BMI (kg/m 2 ) (median, range) 23 (18–26) 24 (19–27)ECG 1. Nonspecific ST-changes (6/25)2. Negative T in leads V 4  to V 6  (6/25)Nonspecific ST-changes (2/10)24-h ECG recording 1. Sinus tachycardia (10/25)2. Supraventricular extrasystolic beats (10/25)3. Ventricular extrasystolic beats (5/25)4. Bigeminy (3/25)5. Couples (2/25)Supraventricular extrasystolic beats (2/10)ECHO (LV dysfunction) 6/25 0CMR (normal LV function) 15/25LVEF 69.4  4.3%LVEDV 131.9  33.0 mlLVESV 40.2  13.6 ml10/10LVEF 70.3  2.5%LVEDV 174.5  31.3 mlLVESV 51.0  14.1 mlCMR (LV dysfunction) 10/25LVEF 45.0  2.9%LVEDV 186.4  46.0 mlLVESV 107.1  29.8 ml0LGE (  ) 18/25 (10 with low LVEF/8 with normal LVEF) 5/10 (all with normal LVEF)Abnormal serum CPK 13/25 (52%) 2/10 (20%) Values are n, median (range), or mean  SD, unless specified otherwise.BMDc  Becker muscular dystrophy carriers; BMI  body mass index; CMR  cardiac magnetic resonance; CPK   creatine protein kinase; DMDc  Duchenne muscular dystrophy carriers; ECG  electrocardiography: ECHO  echocardiography; LGE  late gadolinium-enhanced; LV  left ventricular; LVEDV  left ventricular end-diastolic volume; LVEF  left ventricular ejection fraction;LVESV  left ventricular end-systolic volume; SBP  systolic blood pressure. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 6 , N O . 4 , 2 0 1 3A P R I L 2 0 1 3 : 5 2 6 – 3 1 Letters to the Editor 527  R E F E R E N C E S 1. Emery A. Duchenne muscular dystrophy or Meryon’s disease. Lancet2001;357:1529.2. Mavrogeni S, Spargias C, Bratis C, et al. Myocarditis as a precipitatingfactor for heart failure: evaluation and 1-year follow-up using cardiovas-cular magnetic resonance and endomyocardial biopsy. Eur J Heart Fail2011;13:830–7.3. Bobo JK, Kenneson A, Kolor K, Brown MA. Adherence to American Academy of Pediatrics recommendations for cardiac care among femalecarriers of Duchenne and Becker muscular dystrophy. Pediatrics 2009;123:e471–5.4. Mavrogeni S, Papavasiliou A, Skouteli E, Magoutas A, Dangas G.Cardiovascular magnetic resonance imaging evaluation of two families with Becker muscular dystrophy. Neuromuscul Disord 2010;20:717–9.5. Yilmaz A, Gdynia HJ, Ludolph AC, Klingel K, Kandolf R, Sechtem U.Images in cardiovascular medicine. Cardiomyopathy in a Duchennemuscular dystrophy carrier and her diseased son: similar pattern revealedby cardiovascular MRI. Circulation 2010;121:e237–9. Interval from the Onset of  Transmitral Flow to AnnularVelocity Is a Marker of LV Filling Pressure Recently, the time interval between the onset of early diastolic transmitralflow velocity (E) and mitral annular velocity (e = ) (T E-e = ) was proposed asa new index representing left ventricular (LV) relaxation. A problem withthemeasurementofT E-e =  wasthatEande = couldnotbemeasuredinthesamebeat.However,anoveldualDopplerechocardiographicmethodhasbeenintroducedthatallowsthemeasurementofbothEande = inthesamebeat (1), and E/e =  and T E-e =  can be instantly calculated. The aims of thisstudy were to: 1) investigate the usefulness of single-beat T E-e =  compared with invasive hemodynamic measurements; and 2) determine the impactof pre-load alterations by leg-positive pressure (LPP) on the relationshipbetween T E-e =  and increased LV filling pressure. We designed a prospective study to assess 42 consecutive patients who underwent catheterization for diagnosis of stable angina pectoris. Twenty-one age- and sex-matched healthy volunteers served as thecontrol group. Patients with atrial fibrillation, valve diseases, severeheart failure, LV systolic dysfunction (LV ejection fraction  40%), ora regional wall motion abnormality at the basal, lateral, or septal region were excluded. A total of 63 pairs of echocardiographic examinations were per-formed at baseline and during LPP. We used an ultrasound machineEUB-7500 (Hitachi Medical Corporation, Kashiwa, Japan). A 5-F Millar transducer with single lumen was introduced into the LV. Tauand LV end-diastolic pressure (LVEDP) were determined from theLV pressure curve, and measurements were performed simultaneously  with the echocardiographic measurements. We customized a commer-cially available leg massage machine (Dr. Medomer DM-5000EX,Medo Industries, Tokyo, Japan) because it could maintain the samepressure loading (90 mm Hg) for 5 min.Values are expressed as mean    SD. The diagnostic ability of echocardiographic parameters to discriminate elevated LVEDP (  16mm Hg) was determined by analysis of receiver-operating character-istic (ROC) curves. Reproducibility was expressed as the intraclasscorrelation coefficients (ICC) in a group of 10 randomly selectedsubjects by 1 observer, and then repeated on 2 separate days by 2investigators. The clinical characteristics and the influence of LPP in both groupsareshownin Table1.ArepresentativecaseisshowninFigure1.There  was a correlation between T E-e =  and LVEDP at baseline (r    0.71,p  0.001) and during LPP (r  0.82, p  0.001). There was also arelationship between the change in LVEDP in response to LPP andthe change in T E-e =  (r  0.50, p  0.001). The T E-e =  (standardizedbeta  0.73, p  0.001 at baseline and standardized beta  0.89, p  0.001 during LPP) was an independent predictor of the LVEDP inmultivariate regression analysis with adjustment for age and sex. AROC curve (area under the curve [AUC]  0.93) was used to select a T E-e =  cutoff of 38 ms (specificity: 91%; sensitivity: 85%) to predictelevated LVEDP (  16 mm Hg) during LPP. For differentiatingelevated LVEDP during LPP, the AUC was significantly higher forthe T E-e =  compared with E/e =  (AUC  0.93 vs. AUC  0.72, p  0.004).TheT E-e = (standardizedbeta  0.42,p  0.011atbaselineandstandardized beta  0.71, p  0.001 during LPP) were also indepen-dent predictors of tau in multivariate regression analysis with adjust-ment for age and sex. The ICC of intraobserver variability was 0.98(p  0.001), and interobserver variability was 0.95 (p  0.001). This study is the first to demonstrate that single-beat T E-e = correlated with invasively measured LV diastolic pressure, and thatthe T E-e =  was a better predictor of LV filling pressure than E/e = . Inaddition, our study showed that T E-e =  is pre-load–dependentcompared with other Doppler parameters of LV diastolic function. T E-e =  could be influenced by pre-load changes, especially withimpaired LV relaxation. We postulate that because the mitral E begins with the crossing of left atrial (LA) and LV pressures, an augmentation of LA pressuremight shorten the time needed for LA and LV pressures to cross, andthis would shorten the isovolumic relaxation time. The onset of e =  isinfluenced by LV active relaxation and the cardiac restoring forces inend diastole. As LV relaxation is delayed and early diastolic suction isreduced, the onset of e =  is delayed and follows the onset of the E wave. Inaddition, an augmentation in pre-load might prolong the duration of systoleanddelaytheonsetofe = .Forthesereasons,T E-e =  wasprolongedby a pre-load increase. The main limitation of this study was the smallnumber of patients with elevated LVEDP at baseline (8 of 42).ElevationofLVEDPprolongsT E-e = ,andthismaybeduetoenhancedearly diastolic mismatch between mitral inflow and annular motion. T E-e = is a sensitive noninvasive index for the estimation of LVEDP, and dualDopplerechocardiographyisapracticalmethodfortheaccuratemeasure-ment of this index in a single beat. Kenya Kusunose, MD, PhD, Hirotsugu Yamada, MD, PhD,*Susumu Nishio, RMS, Rina Tamai, RMS, Toshiyuki Niki, MD,Koji Yamaguchi, MD, PhD, Yoshio Taketani, MD,Takashi Iwase, MD, PhD, Takeshi Soeki, MD, PhD,Tetsuzo Wakatsuki, MD, PhD, Masataka Sata, MD, PhD *Department of Cardiovascular Medicine, Tokushima University Hospital, 2-50-1 Kuramoto, Tokushima, Japan.  E-mail: yamadah@tokushima-u.ac.jp . http:dx.doi.org/10.1016/j.jcmg.2012.10.025 J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 6 , N O . 4 , 2 0 1 3A P R I L 2 0 1 3 : 5 2 6 – 3 1 Letters to the Editor528
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